Project Summary Cancers are a leading cause of death and in efforts to reduce their incidence, as well as their recurrence after chemotherapy and/or radiation, physicians and scientists have repeatedly sought to increase the immunogenicity of cancers so as to promote host anti-cancer immune responses. These efforts were largely unsuccessful, likely in part because of the role of host Foxp3+ T regulatory (Treg) cells in limiting anti-tumor immune responses. Hence, the ability to decrease Treg function may be of major therapeutic significance if this can be done incrementally, and without full-scale depletion of Tregs that are essential to the maintenance of immune homeostasis and for the prevention of autoimmunity. Deubiquitinase enzymes (DUBs) reverse the effects of ubiquitination and thereby stabilize the expression of various proteins that often are otherwise degraded via the proteasome. The effects of genetic or pharmacologic targeting of various DUBs on immune responses are largely unknown. Using a novel screening approach, we have developed genetic and pharmacologic data that point to a key role for the DUB, USP7, in control of murine Treg suppression in vitro and in vivo, without concomitant suppression of protective T cell responses. With a sharp focus on the translational potential of these findings, we propose to determine the effects of USP7 inhibition in murine models of lung cancer, using genetic and pharmacologic approaches. In particular, our studies in immunocompetent hosts will assess whether USP7 targeting can dampen Treg functions and allow host immune responses to now limit the growth and spread of tumors. Our studies could have major consequences for the development of new strategies for immunotherapy in patients with malignancies, and may also have relevance to the management of patients with HIV or other chronic infections.